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    Clinical Trial Results:
    Randomized, 16-Week, Multi-Phase, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Fulranumab as Adjunctive Therapy in Subjects with Signs and Symptoms of Osteoarthritis of the Hip or Knee

    Summary
    EudraCT number
    2014-003224-40
    Trial protocol
    DE   ES   CZ   HU   SE   PL   GB  
    Global end of trial date
    19 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    42160443PAI3007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02301234
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development LLC
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry group, Janssen Research & Development LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the safety, and tolerability of fulranumab subcutaneous (SC) injections compared with placebo SC injections in subjects treated with standard of care who had signs and symptoms of osteoarthritis (OA) of the hip or knee that were not adequately controlled by their current pain therapy and who were planning a joint replacement surgery.
    Protection of trial subjects
    Safety was evaluated throughout the study and included monitoring of adverse events (AE), clinical laboratory testing, vital sign collection (including orthostatic testing), neurologic evaluation (abbreviated neurologic examination including an assessment of pupillary light reflex and signs consistent with carpal tunnel syndrome, Total Neuropathy Score-nurse [TNSn], Mini Mental State Examination [MMSE], autonomic nervous system dysfunction history, and carpal tunnel syndrome questionnaire), joint-related event evaluations (joint examinations and radiographs), numerical rating scale (NRS) for nonstudy joint pain, electrocardiograms (ECGs), physical examinations, and injection-site reactions. This study was conducted in accordance with the ethical principles that have their origin in the declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United States: 58
    Worldwide total number of subjects
    109
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    57
    From 65 to 84 years
    51
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 111 subjects were randomized: 37 in the placebo group, 36 in the fulranumab (FUL) 1 mg every 4 Weeks (Q4wk) group, and 38 in the FUL 3 mg Q4wk group. There were 2 subjects who were randomized but were not treated.

    Period 1
    Period 1 title
    Double-Blind
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 weeks) for 16 weeks during the double-blind treatment phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 4 placebo SC injections (one injection every 4 weeks) for 16 weeks during the double-blind treatment phase.

    Arm title
    Fulranumab 1 milligram (mg)
    Arm description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 1 mg during the double-blind treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Fulranumab 1 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during the double-blind treatment phase.

    Arm title
    Fulranumab 3 mg
    Arm description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 3 mg during the double-blind treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Fulranumab 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during the double-blind treatment phase.

    Number of subjects in period 1
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Started
    37
    35
    37
    Completed
    15
    10
    19
    Not completed
    22
    25
    18
         Study terminated by sponsor
    19
    19
    17
         Adverse event, non-fatal
    -
    -
    1
         Consent withdrawn by subject
    2
    6
    -
         Subjects medical records revealed subject has HIV
    1
    -
    -
    Period 2
    Period 2 title
    24 Week Follow-up Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    Subjects who received placebo in treatment phase were followed for 24 weeks in this period.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Fulranumab 1 mg
    Arm description
    Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks in this period.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Fulranumab 3 mg
    Arm description
    Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks in this period.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Placebo Fulranumab 1 mg Fulranumab 3 mg
    Started
    22
    20
    27
    Completed
    12
    13
    19
    Not completed
    10
    7
    8
         Physician decision
    -
    1
    -
         Adverse event
    1
    -
    -
         Study terminated by sponsor
    8
    6
    5
         Consent withdrawn by subject
    1
    -
    3
    Period 3
    Period 3 title
    Limited Safety Follow-up (LSFU)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects who received placebo in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Fulranumab 1 mg
    Arm description
    Subjects who received fulranumab 1 mg in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Fulranumab 3 mg
    Arm description
    Subjects who received fulranumab 3 mg in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    Placebo Fulranumab 1 mg Fulranumab 3 mg
    Started
    6
    2
    2
    Completed
    5
    1
    2
    Not completed
    1
    1
    0
         Study terminated by sponsor
    -
    1
    -
         Consent withdrawn by subject
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 weeks) for 16 weeks during the double-blind treatment phase.

    Reporting group title
    Fulranumab 1 milligram (mg)
    Reporting group description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 1 mg during the double-blind treatment phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 3 mg during the double-blind treatment phase.

    Reporting group values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg Total
    Number of subjects
    37 35 37 109
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    17 21 19 57
        From 65 to 84 years
    20 13 18 51
        85 years and over
    0 1 0 1
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    65 (49 to 81) 61 (43 to 85) 64 (38 to 82) -
    Title for Gender
    Units: subjects
        Female
    27 27 16 70
        Male
    10 8 21 39

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 weeks) for 16 weeks during the double-blind treatment phase.

    Reporting group title
    Fulranumab 1 milligram (mg)
    Reporting group description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 1 mg during the double-blind treatment phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    Subjects received 4 SC injections (one injection every 4 weeks) of fulranumab 3 mg during the double-blind treatment phase.
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo in treatment phase were followed for 24 weeks in this period.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks in this period.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks in this period.
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    Subjects who received fulranumab 1 mg in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    Subjects who received fulranumab 3 mg in treatment phase were followed for up to 24 weeks after the last injection of study drug in this follow-up phase. Subjects who discontinued from the 24-week follow-up phase were asked to enter the LSFU phase.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability [1]
    End point description
    An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
    End point type
    Primary
    End point timeframe
    Baseline Up to 16 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for this outcome measure due to the small number of subjects subsequent to premature closure of the study.
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    37
    35
    37
    Units: subjects
    20
    23
    20
    No statistical analyses for this end point

    Secondary: Change from Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Pain Subscale Score

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    End point title
    Change from Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Pain Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function are rated on a scale of 0-10, where 0=no pain to 10=extreme pain in the WOMAC pain subscale score. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    37
    35
    37
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline (n=37,35,37)
    7.49 ± 1.273
    7.41 ± 0.982
    7.36 ± 0.958
        Change at Week 5 (n=35,33,36)
    -1.78 ± 1.67
    -2.35 ± 2.402
    -2.87 ± 1.93
        Change at Week 9 (n=30,23,28)
    -2.03 ± 2.198
    -3.06 ± 2.491
    -3.19 ± 2.257
        Change at Week 13 (n=22,18,22)
    -3.09 ± 2.181
    -3.98 ± 2.515
    -3.87 ± 2.396
        Change at Week 17 (n=17,16,17)
    -2.95 ± 1.906
    -2.73 ± 2.399
    -3.36 ± 2.048
        Change at DB-LOCF (n=35,34,36)
    -2.32 ± 2.46
    -2.8 ± 2.6
    -2.89 ± 1.973
    No statistical analyses for this end point

    Secondary: Change from Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Physical Function Subscale Score

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    End point title
    Change from Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Physical Function Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function is rated on a scale of 0-10, where 0=no difficulty to 10=extreme difficulty in performing daily activities in the WOMAC physical function subscale score. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    37
    35
    37
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline (n=37,35,37)
    7.5835 ± 1.20587
    7.3647 ± 0.94612
    7.4149 ± 0.9491
        Change at Week 5 (n=35,33,36)
    -1.8504 ± 1.61129
    -2.3369 ± 2.48665
    -2.8644 ± 2.15375
        Change at Week 9 (n=30,23,28)
    -2.0667 ± 2.17659
    -3.0384 ± 2.50514
    -3.145 ± 2.24025
        Change at Week 13 (n=22,18,22)
    -2.9759 ± 1.97585
    -3.9314 ± 2.7548
    -3.7032 ± 2.38642
        Change at Week 17 (n=17,16,17)
    -2.7439 ± 1.92551
    -2.7721 ± 2.37119
    -3.5087 ± 2.31597
        Change at DB-LOCF (n=35,34,36)
    -2.2336 ± 2.28552
    -2.6869 ± 2.62679
    -2.8235 ± 2.10876
    No statistical analyses for this end point

    Secondary: Change From Baseline to DB-LOCF in WOMAC Stiffness Subscale Score

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    End point title
    Change From Baseline to DB-LOCF in WOMAC Stiffness Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function is rated on a scale of 0-10, where 0=no stiffness to 10=extreme stiffness in the WOMAC stiffness subscale score. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    37
    35
    37
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline (n=37,35,37)
    7.3 ± 1.984
    7.26 ± 1.268
    7.24 ± 1.342
        Change at Week 5 (n=35,33,36)
    -2.04 ± 1.961
    -2.41 ± 2.112
    -2.53 ± 2.378
        Change at Week 9 (n=30,23,28)
    -2.25 ± 2.153
    -2.93 ± 2.347
    -2.82 ± 2.622
        Change at Week 13 (n=22,18,22)
    -3.25 ± 2.022
    -3.94 ± 2.673
    -3.05 ± 2.815
        Change at Week 17 (n=17,16,17)
    -2.94 ± 1.886
    -2.56 ± 2.358
    -3.24 ± 2.699
        Change at DB-LOCF (n=35,34,36)
    -2.39 ± 2.298
    -2.6 ± 2.351
    -2.54 ± 2.328
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Double-blind Phase in Short-Form-36 Health Survey (SF-36) Subscale Score

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    End point title
    Change From Baseline Through Double-blind Phase in Short-Form-36 Health Survey (SF-36) Subscale Score
    End point description
    The Short Form-36 (SF-36) is a self-administered, generic, 36-item questionnaire designed to evaluate 8 domains of functional health and well being: physical and social functioning, physical and emotional role (rolephysical, role-emotional) limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).
    End point type
    Secondary
    End point timeframe
    Baseline through double-blind phase
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: units on scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [2] - Analysis of this endpoint was not done because the program was terminated.
    [3] - Analysis of this endpoint was not done because the program was terminated.
    [4] - Analysis of this endpoint was not done because the program was terminated.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Additional Analgesics Medication Use Through Double-blind Phase

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    End point title
    Number of Subjects With Additional Analgesics Medication Use Through Double-blind Phase
    End point description
    Use other OA pain medication was recorded weekly during the study. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'N' signifies number of subjects analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 67 weeks
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    22
    21
    21
    Units: subjects
    23
    23
    23
    No statistical analyses for this end point

    Secondary: Number of Subjects who Developed Antibodies to Fulranumab

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    End point title
    Number of Subjects who Developed Antibodies to Fulranumab
    End point description
    Number of subjects who developed antibodies to fulranumab were assessed.
    End point type
    Secondary
    End point timeframe
    Up to 67 weeks
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    37
    35
    37
    Units: subjects
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentrations for Fulranumab

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    End point title
    Plasma Concentrations for Fulranumab
    End point description
    Plasma Concentrations for Fulranumab were assessed.
    End point type
    Secondary
    End point timeframe
    Up to 67 weeks
    End point values
    Placebo Fulranumab 1 milligram (mg) Fulranumab 3 mg
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: nanogram/milliliter (ng/mL)
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [5] - Due to less number of subjects treated, only few samples were collected. No PK analyses was done.
    [6] - Due to less number of subjects treated, only few samples were collected. No PK analyses was done.
    [7] - Due to less number of subjects treated, only few samples were collected. No PK analyses was done.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 67 weeks
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received 4 placebo subcutaneous (SC) injection (one injection every 4 week) for 16 weeks during double blind treatment phase (Period 1) and were followed-up for 24 weeks in follow-up phase (Period 2). Subjects who received placebo and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed-up for up to 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed-up for 24 weeks in LSFU (Period 3).‌‌

    Reporting group title
    fulranumab (FUL) 1 mg
    Reporting group description
    Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase and were followed-up for 24 weeks in follow-up phase (Period 2).Subjects who received Fulranumab 1 mg and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed-up for up to 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed-up for 24 weeks in LSFU (Period 3).‌‌‌

    Reporting group title
    FUL 3 mg
    Reporting group description
    Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during double-blind treatment phase and were followed-up for 24 weeks in follow-up phase (Period 2).Subjects who received Fulranumab 3 mg and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed-up for up to 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed-up for 24 weeks in LSFU (Period 3).‌‌‌‌

    Serious adverse events
    Placebo fulranumab (FUL) 1 mg FUL 3 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 35 (8.57%)
    1 / 37 (2.70%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal Cancer Stage Iv
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Thrombosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Spigelian Hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo fulranumab (FUL) 1 mg FUL 3 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 37 (56.76%)
    31 / 35 (88.57%)
    26 / 37 (70.27%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 35 (14.29%)
    2 / 37 (5.41%)
         occurrences all number
    3
    6
    2
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    1
    0
    2
    Peripheral Coldness
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Feeling Hot
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    0
    Injection Site Induration
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Oedema Peripheral
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    0
    Peripheral Swelling
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Vessel Puncture Site Haematoma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    3
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Uterine Prolapse
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Back Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Burns First Degree
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    2
    1
    0
    Epicondylitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Fall
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    4
    1
    0
    Foot Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Joint Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Injection Related Reaction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Ligament Sprain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle Strain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Nail Avulsion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Skin Abrasion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Stress Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Thermal Burn
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Traumatic Haematoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood Pressure Diastolic Decreased
         subjects affected / exposed
    6 / 37 (16.22%)
    5 / 35 (14.29%)
    8 / 37 (21.62%)
         occurrences all number
    9
    5
    12
    Blood Pressure Increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Blood Pressure Systolic Decreased
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 35 (11.43%)
    4 / 37 (10.81%)
         occurrences all number
    7
    8
    5
    Electrocardiogram Abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Heart Rate Decreased
         subjects affected / exposed
    6 / 37 (16.22%)
    10 / 35 (28.57%)
    6 / 37 (16.22%)
         occurrences all number
    8
    12
    6
    Heart Rate Increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    0
    1
    Weight Increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    3
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal Congestion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary Mass
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    1
    Decreased Vibratory Sense
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness Postural
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    3
    1
    2
    Hypoaesthesia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    1
    Presyncope
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    1
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Hiatus Hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal Prolapse
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth Impacted
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Skin Burning Sensation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Skin Lesion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 35 (11.43%)
    0 / 37 (0.00%)
         occurrences all number
    1
    5
    0
    Back Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Bursitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Joint Effusion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Joint Swelling
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 35 (8.57%)
    2 / 37 (5.41%)
         occurrences all number
    2
    4
    2
    Myalgia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    2
    1
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 35 (5.71%)
    3 / 37 (8.11%)
         occurrences all number
    2
    2
    3
    Periarthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    1
    Spinal Osteoarthritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Synovial Cyst
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 35 (8.57%)
    0 / 37 (0.00%)
         occurrences all number
    0
    3
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Diverticulitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes Zoster
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Lower Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 35 (2.86%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 35 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2014
    Amendment INT-1 included the following changes: assessment for efficacy variables of WOMAC and PGA were added based on health authority feedback for efficacy analysis after discontinuation of treatment; clarification to improve performance of assessments and conduct of study; and minor errors were noted.
    06 Feb 2015
    Amendment INT-2 included the: Clarification and consistency to labeling and guidelines.
    09 Feb 2015
    Amendment INT-3 included the following changes: Addition of criteria to be used to alert the IDMC to review events of interest (neurologic) and reference to criteria to be used by the IDMC for decisions related to the further conduct of the study based on prespecified safety based criteria (for joint replacement, neurologic, sympathetic, hepatic and renal events of interest, ie, stopping criteria); clarification to improve performance of assessments and conduct of study and minor errors were noted.
    09 Jul 2015
    Amendment INT-4 included the following changes: Changes requested by ethics committees and health authorities to clarify study conduct and/or subject; Changes to clarify study conduct.
    14 Dec 2015
    Amendment INT-5 included the following changes: Respond to regulatory authority request to prohibit resumption of dosing for subjects who develop joint events of interests; respond to regulatory authority requests to include an assessment for carpal tunnel syndrome (CTS), at each clinic visit during the treatment periods, and at dedicated clinic visits during the safety follow-up period; clarification of what is acceptable as opioid failure in U.S. and Canada as per FDA request; clarification that a medication that is contraindicated will qualify as a failure due to intolerability; clarify that fasting serum and urine samples are preferred for biomarker analysis; and minor errors were noted.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to discontinuation of fulranumab program by sponsor for strategic reasons, the study was closed to enrollment before being fully enrolled. Hence, the study results are limited to descriptive summaries of all safety data and select efficacy data.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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